Neutrophil mobilization via plerixafor-mediated CXCR4 inhibition arises from lung demargination and blockade of neutrophil homing to the bone marrow

Blood neutrophil homeostasis is essential for successful host defense against invading pathogens. Circulating neutrophil counts are positively regulated by CXCR2 signaling and negatively regulated by the CXCR4-CXCL12 axis. In particular, G-CSF, a known CXCR2 signaler, and plerixafor, a CXCR4 antagonist, have both been shown to correct neutropenia in human patients. G-CSF directly induces neutrophil mobilization from the bone marrow (BM) into the blood, but the mechanisms underlying plerixafor-induced neutrophilia remain poorly defined. Using a combination of intravital multiphoton microscopy, genetically modified mice and novel in vivo homing assays, we demonstrate that G-CSF and plerixafor work through distinct mechanisms. In contrast to G-CSF, CXCR4 inhibition via plerixafor does not result in neutrophil mobilization from the BM. Instead, plerixafor augments the frequency of circulating neutrophils through their release from the marginated pool present in the lung, while simultaneously preventing neutrophil return to the BM. Our study demonstrates for the first time that drastic changes in blood neutrophils can originate from alternative reservoirs other than the BM, while implicating a role for CXCR4-CXCL12 interactions in regulating lung neutrophil margination. Collectively, our data provides valuable insights into the fundamental regulation of neutrophil homeostasis, which may lead to the development of improved treatment regimens for neutropenic patients.This research was funded by SIgN, A*STAR, Singapore. C.N.Z. Mattar and J.K.Y. Chan received salary support from the National Medical Research Council of Singapore (NMRC/TA/003/2012 and NMRC/CSA/012/2009, respectively).S

World Heart Federation Roadmap on Atrial Fibrillation – A 2020 Update

The World Heart Federation (WHF) commenced a Roadmap initiative in 2015 to reduce the global burden of cardiovascular disease and resultant burgeoning of healthcare costs. Roadmaps provide a blueprint for implementation of priority solutions for the principal cardiovascular diseases leading to death and disability. Atrial fibrillation (AF) is one of these conditions and is an increasing problem due to ageing of the world’s population and an increase in cardiovascular risk factors that predispose to AF. The goal of the AF roadmap was to provide guidance on priority interventions that are feasible in multiple countries, and to identify roadblocks and potential strategies to overcome them.Since publication of the AF Roadmap in 2017, there have been many technological advances including devices and artificial intelligence for identification and prediction of unknown AF, better methods to achieve rhythm control, and widespread uptake of smartphones and apps that could facilitate new approaches to healthcare delivery and increasing community AF awareness. In addition, the World Health Organisation added the non-vitamin K antagonist oral anticoagulants (NOACs) to the Essential Medicines List, making it possible to increase advocacy for their widespread adoption as therapy to prevent stroke. These advances motivated the WHF to commission a 2020 AF Roadmap update. Three years after the original Roadmap publication, the identified barriers and solutions were judged still relevant, and progress has been slow.This 2020 Roadmap update reviews the significant changes since 2017 and identifies priority areas for achieving the goals of reducing death and disability related to AF, particularly targeted at low-middle income countries. These include advocacy to increase appreciation of the scope of the problem; plugging gaps in guideline management and prevention through physician education, increasing patient health literacy, and novel ways to increase access to integrated healthcare including mHealth and digital transformations; and greater emphasis on achieving practical solutions to national and regional entrenched barriers. Despite the advances reviewed in this update, the task will not be easy, but the health rewards of implementing solutions that are both innovative and practical will be great

Catheter Ablation of Atrial Fibrillation

Atrial fibrillation is the most common arrhythmia encountered in clinical practice and can result in significant morbidity and mortality. Catheter ablation has become a feasible therapeutic option for the management of this complex and challenging arrhythmia. In this article, we have discussed the mechanism of atrial fibrillation, different imaging modalities used for atrial fibrillation ablation, different ablation strategies targeting non-pulmonary veins, complications associated with atrial fibrillation ablation and its management, alternative energy sources for ablation and new antiarrhythmic drugs

Catheter Ablation for Atrial Fibrillation: A Review of the Literature

Atrial fibrillation (AF) is the most frequent arrhythmia seen in clinical practice. The incidence of persistent and permanent AF will likely continue to increase as the population ages and as patients with structural heart disease live longer. Until recently, antiarrhythmic medications have been the only commonly employed treatment for maintaining sinus rhythm. However, antiarrhythmic medications have a modest long-term efficacy and the potential for serious side effects. Radiofrequency (RF) catheter ablation is now emerging as a viable alternative to antiarrhythmic medications in maintaining sinus rhythm in patients with AF. A number of different ablation strategies have been used including pulmonary vein isolation, targeting of fractionated electrograms, compartmentalising the atria with linear lesions and various combinations and modifications of these lesion sets. The variation in success within and between techniques suggests that the optimal ablation technique for AF is unclear. The general consensus for patients with paroxysmal atrial fibrillation is to achieve electrical isolation of the pulmonary veins (PVs). In patients with non-paroxysmal AF, PV isolation alone appears to be insufficient. In addition, the structural and electrophysiological changes that have typically occurred at the advanced stage of AF lend greater importance to the identification and ablation of atrial myocardial substrate-driven “sources”. Further efforts are needed to develop better techniques and tools to safely, effectively, and permanently isolate the pulmonary veins, to identify which sites are critical to the maintenance of AF, and to create durable lesions to interrupt intra-arterial reentry. In this review, the rationale and outcomes of rhythm management with drugs and ablation strategies targeting various mechanisms of AF based on our current understanding are discussed

Review on Non-Invasive Risk Stratification of Sudden Cardiac Death

Sudden cardiac death (SCD) is one of the most significant and challenging problems facing modern medicine today given its unpredictable nature. The evaluation of the patient at risk for sudden cardiac death still remains a complex task. The use of ICDs (implantable cardioverter defibrillators) remains the mainstay of primary prevention of sudden cardiac death. However, much remains to be determined on how best to identify patients at high risk of sudden cardiac death who would most benefit from ICD implantations. This paper will review the current issues in the risk assessment of sudden cardiac death and non-invasive markers of sudden death

Factors Influencing Prescribing of Statins in Singapore Compared to Queensland, Australia

HMG-CoA reductase inhibitors (statins) are widely prescribed for dyslipidaemia with established benefits in reducing cardiovascular disease mortality and morbidity. Controversy remains surrounding statin use in low risk patients and patients of certain ethnicities. The aim of this study was to identify factors which influence the prescribing of statins by interviewing doctors from Queensland, Australia and Singapore. Purposive interviews were conducted with prescribers in Queensland Australia (n=20) and Singapore (n=21) to determine factors influencing statin prescribing. Cost, availability of generics and statin potency were major factors significantly influencing Singaporean prescribers compared to Australian prescribers (p<0.05). Although not significant, the potential for drug interactions also impacted statin prescribing in Singapore compared to Australia (p=0.0516). Cost and statin potency were major factors influencing the prescribing of statins in Singapore compared to Australia. Patients may be prescribed the cheaper, less potent statins potentially resulting in reduced patient benefits